1. Field of the Invention
The present invention relates generally to novel classes of cytoprotective steroid (cyclopentanophenanthrene-related) compounds, as well as to compositions and methods for using such compounds to treat degenerative disorders including degenerative diseases and related conditions, and in particular, disorders associated with undesirable cell death or cell damage.
2. Description of the Related Art
Numerous degenerative diseases, disorders and conditions afflicting humans and animals are characterized by detrimental damage to tissues and cells, often resulting in undesirably compromised cellular activity and frequently leading to cell death. Recent technological refinements provide insights into a detailed molecular understanding of such cytodegeneration, including, inter alia, appreciation of the roles of: genetic and environmental factors; reactive free radicals (e.g., reactive oxygen species); excitotoxic, autoimmune and inflammatory mechanisms; and characterization of cellular death processes such as apoptosis and necrosis. The scope of degenerative diseases, and their costs to society, are extensive, with massive impacts on the basic quality of life and on human productivity.
Degenerative disorders include a large number of acute, relapsing/remitting and/or chronic debilitating conditions that feature cell death or cellular damage, such as neurological and neurodegenerative diseases (e.g., Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, mild cognitive impairment, etc.), circulatory and cardiac disease (e.g., atherosclerosis, diabetes, ischemia, heart failure, etc.), cancer, autoimmune and inflammatory diseases, inherited genetic diseases and disorders, traumatic injuries, arthritis, metabolic and digestive diseases, ophthalmologic diseases or injuries, dermatological, musculoskeletal, endocrine, renal, hepatic, gastroinstestinal, and respiratory disorders, and many others.
The estrogen steroid hormones (e.g., 17-β-estradiol, estrone) and structurally related derivative compounds have attracted considerable interest as candidate cytoprotectants for use in the treatment of degenerative disorders, and in particular as neuroprotectants, based on a number of chemical and biological properties (see, e.g., U.S. Pat. Nos. 6,692,763, 6,511,969, 6,420,353, 6,334,998, 6,333,317, 6,258,856, 6,232,326, 6,172,056, 6,089,941, 5,990,177, 5,866,561, 5,521,168, 5,512,557, U.S. 2004/0067923, WO 03/072109, WO 03/072110, U.S. 2004/0043410, U.S. 2003/0186954, U.S. 2003/0176409, U.S. 2003/0130303, U.S. 2003/0050295, U.S. 2003/0049838, U.S. 2002/0183299, U.S. 2002/0165213, U.S. 2002/0028793, U.S. 2002/0022593, U.S. 2001/0051602, WO 03/015704, U.S. Pat. No. 4,897,389, EP 753,300, U.S. Pat. No. 5,554,603; see also Dykens et al., 2003 Exp. Gerontol. 38(1-2):101-107; Wang et al., 2003 Invest. Ophthalmol. Vis. Sci. 44(5):2067-75; Garcia-Segura et al., 2001 Prog. Neurobiol. 63(1):29-60; Deshpande et al., 2000 Ind. J. Physiol. Pharmacol. 44(1)43-49; Behl et al., 1995 Biochem. Biophys. Res. Commun. 216:473-82; McCullough et al., 2003 Trends Endocrinol. Metab. 14(5):228-235; Kulkami et al., 2002 Arch. Women Ment. Health 5:99-104; Zemlyak et al., 2002 Brain Res. 958:272-76; Kompoliti, 2003 Front. Biosci. 8:391-400; Mooradian, 1993 J. Steroid Biochem. Molec. Biol. 45(6):509-511; Kupina et al., 2003 Exp. Neurol. 180:55-73).
Despite these efforts, a number of avenues remain unexplored with regard to the relevance of these compounds to particular applications or disease indications, including the relationship of chemical properties to desired biological, physiological and/or pharmacological properties, the relative ease of synthesis (or of isolation in the case of naturally derived estrogen compounds, for which purity and lot-to-lot consistency may also pose challenges), efficacy as cytoprotectants, stability, bioavailability, adaptability to suitable formulations, and other considerations. Recent progress in this area has been described, for example in U.S. Pat. No. 6,844,456, U.S. 2002/0132802, U.S. 2002/0035100, U.S. Pat. Nos. 5,554,601, 5,824,672, 5,843,934, 5,859,001, 5,877,169, 5,939,407, 5,972,923, 6,172,088, 6,197,833, 6,207,658, 6,319,914, 6,326,365, 6,339,078, 6,350,739, WO 01/10430, WO 02/13870, U.S. 2003/0105167. Clearly, however, there remains a need for additional compounds that can be optimized for use as cytoprotectants, including demonstration of the suitability of such compounds for use in the treatment of degenerative disorders and diseases in a physiologically relevant context. The present invention addresses this need by providing compositions and methods for therapeutically beneficial cytoprotection, and offers other related advantages.